1. Technical Field
The present disclosure relates to the treatment of cancer. More particularly, the disclosed invention relates to the use of novel bi-functional inhibitors against histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR), and theirs uses as medicaments for the treatment or prophylaxis of diseases and/or conditions associated with inhibition and/or suppression of HDACs and HMGR, such as cancers.
2. Description of Related Art
Acetylation and deacetylation of histones are carried out by histone acetyl transferases (HAT) and histone deacetylases (HDACs). The state of acetylation of histones is an important determinant of gene transcription. Deacetylation is generally associated with reduced transcription of genes whereas increased acetylation of histones as induced by the action of HDAC inhibitors (HDACi) results in greater transcription of genes. Thus, HDAC inhibitors affect multiple processes in the cell which are likely to depend upon the dynamic state of the cell with respect to its capabilities of replication and differentiation.
In another aspect, statins have recently been shown to be effective for cancer prevention in observational, preclinical, and certain randomized controlled studies. Statins, such as lovastatin and mevastatin, are known to reduce serum cholesterol levels through competitive inhibition at 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). The HMGR inhibitors (HMGRi) have been used to decrease the incidence of cardiovascular and cerebrovascular disorders, and to prevent cardiovascular disease (CVD). Statins possess an established record of safety and efficacy in human CVD prevention.
It has been reported that the combination use of anticancer agents with statins may reduce side effects to attain better treatment of cancers. Furthermore, the in vitro experiment using combination of HDACi and HMGRi exhibited a synergistic induction on apoptosis of HeLa cells.
Given the prior knowledge relating to HDACi and HMGRi, inventors of the present disclosure conceived that concurrent inhibition of HDAC and HMGR would be a promising approach for cancer treatment. However, using multi-component drug-cocktails for therapeutics has some drawbacks, such as complex pharmacokinetics, unpredictable drug-drug interaction, and formulation problems due to different solubilities of individual drugs. Alternatively, to design a single compound that simultaneously modulates multiple targets, dubbed designed multiple ligand (DML), has become an emerging paradigm for drug discovery. DMLs constructed by incorporation of HDACi into other active agents targeting inosine monophosphate dehydrogenase, (Chen, L., et al. J. Med. Chem. 2007, 50, 6685. Chen, L., et al. Bioorg. Med. Chem. 2010, 18, 5950.) nuclear vitamin D receptor, (Tavera-Mendoza, L. E., et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 8250.) tyrosine kinase receptor (Mahboobi, S., et al. J. Med. Chem. 2009, 52, 2265. Cai, X., et al. J. Med. Chem. 2010, 53, 2000.) or topoisomerase II (Guerrant, W., et al. J. Med. Chem. 2012, 55, 1465.) have been tested in cancer treatments. (O'Boyle, N. M. & Meegan, M. J. Curr. Med. Chem. 2011, 18, 4722.)
Therefore, it is the aim of the present disclosure to provide novel dual-action compounds that target both HDACs and HMGRs. These compounds are thus potential lead compounds for preparing or manufacturing medicaments to prevent or treat various diseases and conditions, in which suppression of HDACs and HMGRs provides beneficial outcomes.